The major goal of this proposal is to better understand immune maturation and its relationship to viral respiratory infection disease severity. Viral respiratory infections (VRI) are a significant health risk to infants. These common childhood infections, for which few therapeutics or effective vaccines exist, result in significant morbidity and mortality during the first 5 years of life. As such, VRIs are a significant public health problem impacting the quality of life of affected children and places increased societal strain in the workplace and on health care utilization. Additionally VRIs appear to have a long lasting health impact, for example in some children resulting in the development of chronic allergic diseases. Uniquely, unpublished data from MESA demonstrate significantly decreased respiratory infections during the first 2 years of life in farm children compared to non-farm children. These effects parallel published findings from around the world that farm exposures lower the risk of childhood allergies and asthma. Notably, the development of allergen sensitization and highest vulnerability to VRIs coincides with the maturation phase of the immune system, and there is evidence that farm exposures enhance development of innate immunity and T regulatory (Treg) cell function. We hypothesize that farm exposures reduce the risk of VRIs in young children by enhancing the development of innate antiviral immunity and Treg function. To test this hypothesis, we will develop a unique birth cohort study from Wisconsin farm and non-farm families within MESA. Functional assays to define innate and Treg cell maturation will be utilized in a longitudinal manner along with surveillance of VRIs and allergic sensitization. A better mechanistic understanding of how environmental exposures promote resistance to VRIs and diminish allergic diseases through effects on immune maturation will allow for development of new strategies to bring benefits of farm exposures to those who live elsewhere. In addition to addressing these research goals, this project will serve as a source of extensively characterized clinical specimens (airway epithelial cells, clinical isolates of rhinoviruses) that will enable mechanistic studies to define host-virus interactions that contribute to the severity of clinical illnesses.